Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma

Abstract

Summary Methenamine (hexamethylenetetramine, hexamine, urotropine) is a compound discovered in 1859, which is still currently being used as a urinary antiseptic. Methenamine is highly soluble in water and polar solvents, and its molecular constitution is similar to adamantane compounds with tetrahedral cage like structure. In acidic conditions, methenamine decomposes to formaldehyde and ammonia. Recently, methenamine has gained a renewal of interest due to antibiotic‐resistant bacteria urinary tract infections; interestingly, bacteria cannot gain resistance to formaldehyde. In 1968, David and Burkitt reported remarkable regression of four Burkitt Lymphoma patients in eight subjects who were treated with septicemine (a solution containing 6.3 g of methenamine iodomethylate and 1 g of methenamine sodium benzoate in 100 cc distilled water). Unfortunately, these striking observations did not gain interest in the medical community; despite experimental models that showed that methenamine synergized with hyperthermia, radiation, and chemotherapy to block cancer growth. As the hypoxic core of tumours have an acidic pH, it would be plausible to expect that methenamine would selectively target dormant, non‐proliferative, and treatment‐resistant cancer clones in large tumours. Moreover, previous data suggests that methenamine can be safely used intravenously and for treatment of infections of the central nervous system. It may therefore be an effective adjuvant in treatment of systemic cancers and glioblastoma.

Targeting Multiresistant Gram-Positive Bacteria by Ruthenium, Osmium, Iridium and Rhodium Half-Sandwich Type Complexes With Bidentate Monosaccharide Ligands

“…Bacterial resistance to registered antibiotics is one of the biggest challenges of mankind ( Hernando-Amado et al, 2019 ; Murray et al, 2022 ) that begs for the discovery of novel antibacterial compounds. There are multiple examples of antibacterial agents that were repurposed as anticancer drugs [e.g., Methenamine ( Altinoz et al, 2019 )], or anticancer medications being repurposed as antibacterial ones, such as platinum(II) remedies. Indeed, cisplatin and carboplatin do have bacteriostatic properties on Acinetobacter , Mycobacteria , and Pseudomonas aeruginosa ( Zhang et al, 2011 ; McCarron et al, 2012 ; Yuan et al, 2018 ) and other pathogens ( Hummell and Kirienko, 2020 ).…”

The resurgence of methenamine hippurate in the prevention of recurrent UTIs in women- a systematic review

“…Although methenamine has been used for more than a century in some countries [9,10], it is still not popular globally. Perhaps because there have only been a few small trials to support its use, and no recommendations are included in the current guidelines.…”

“…Although there is no recommendation for methenamine hippurate in the latest guidelines, it has long been used as a urinary antiseptic [9,10] in the UK and in other countries [11,12,13,14]. Two recent trials, the alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women (ALTAR) trial [16 & ] (an alternative to prophylactic antibiotics for the treatment of rUTIs in women) and the trial conducted by Botros et al in the US [15], have renewed interest in the use of methenamine hippurate as an alternative to low-dose daily antibiotic prophylaxis for the prevention of rUTIs in women.…”

“…Methenamine was first used as a urinary antiseptic in 1894 [9,10]. It is a pro-drug that, in an acidic environment, degrades into formaldehyde and ammonia.…”

Antibacterial and cytotoxic performance of methenamine‐based poly(lactic acid)/poly(ethylene glycol) (PLA/PEG) composite films

“…It was first isolated in 1859 and is still utilized today as a urinary antibacterial agent that can be utilized as either MA mandelate or MA hippurate preparations. [32][33][34][35][36][37] In order to reduce resource waste and environmental pollution, food packaging materials must have effective antibacterial properties as well as biodegradability. PLA is the most researched as a very attractive polymer for food packaging applications.…”